Despite the hastily called press conference on Tuesday, the late-night meetings, and the growing worry over a potentially fatal side effect, the decision to pause the use of one of the three Covid-19 vaccines available in the United States was a relatively easy one.
Figuring out how to unpause, though—that’s going to be a lot trickier.
The public health community had some hope that the Centers for Disease Control and Prevention might find a fast path through the data fog. But that vanished late Wednesday, when an emergency meeting of the CDC’s Advisory Committee on Immunization Practices ended without a recommendation. Amid a global pandemic and a race for mass vaccinations, the pause continues pausing.
The vaccine in question is the one made by Johnson & Johnson and Janssen, effective in just a single dose and tolerant of higher storage temperatures than the finicky, two-dose vaccines from Pfizer and Moderna. But one side effect is dangerous blood clotting in the brain, weirdly accompanied by low levels of platelets, the blood component that’s usually responsible for clotting. Technically, the condition’s a cerebral venous sinus thrombosis (that’s the clot in the veins carrying blood away from the brain—basically a stroke) with thrombocytopenia (that’s the low platelet count). Similar issues have shown up in a couple hundred people who got an AstraZeneca vaccine approved in Europe but not the US; researchers studying the problem call it vaccine-induced immune thrombotic thrombocytopenia. After more than 7 million doses of the J&J vaccine administered in the US, just six cases of VITT have shown up, all in women under 50 years old.
On the one hand: That’s one-in-a-million odds! But on the other hand: That’s very disconcerting. So on Tuesday morning, officials from the Food and Drug Administration and the CDC recommended a total and complete shutdown on J&J shots until they could figure out what the hell is going on. “Out of an abundance of caution, we’re recommending a pause in the use of the Johnson & Johnson Covid vaccine,” said Janet Woodcock, acting director of the FDA, at the Tuesday briefing. “These events appear to be extremely rare. However, Covid-19 vaccine safety is a top priority for the federal government, and we take all reports of adverse events following vaccination very seriously.”
J&J was on board, too. “We have been working closely with medical health experts and health authorities, and we strongly support the open communication of this information to health care professionals and the public,” read a company statement posted online.
Biden administration health officials promised transparency and honesty in the fight against Covid, and this is what that looks like. But it’s also a real problem in the making. The Johnson & Johnson vaccine was supposed to be the cheap-and-easy one, useful for the most at-risk populations and the ones hardest to reach in the US. It’s also an alternative to more expensive, two-dose mRNA vaccines for the rest of the world, where vaccination rates lag far behind those in the US. Losing it would be a blow to the fight against the pandemic.
Worse, if people are already hesitant to get vaccinated, the FDA and CDC saying one vaccine might give people strokes probably won’t help get more sleeves rolled up—even if the regulators come around later and say that it’s fine, or worth the risk, or only dangerous in certain subpopulations. “Public confidence in this vaccine will take a hit no matter what. I think it was a necessary step to take, given the information we knew and the fact that the treatment required is atypical,” says Jason Schwartz, a health policy professor at the Yale School of Public Health. “There’s going to be a lot of work to do to restore enthusiasm for this vaccine.”
The public health world was ready for something like this. They just didn’t know what the something would be. “When these vaccines kicked off to the world’s population, to billions of people, we knew there would be unanticipated side effects,” says Eric Topol, director of the Scripps Research Translational Institute. “These are so rare—the Johnson & Johnson one is one in a million, the AstraZeneca is one in a hundred thousand, ballpark. That’s pretty good. It doesn’t provide any solace to the one, but it should provide lots of solace to the many.”
Still, it won’t be easy to get that message across, especially when the numbers don’t yet tell the whole story. Regulators and vaccine researchers are still waiting for the most basic information about the mechanism behind the clots, the subpopulations that might be most vulnerable, and the real frequency of these dangerous clots.
The J&J and AstraZeneca vaccines both encode the “spike protein” on the surface of the virus that causes Covid-19. The vaccines serve up that bit of biochemical code to a person’s immune system via a different virus, specifically adenoviruses modified into “vectors” that’ll fly the virological cargo. That association—between blood clots and Covid vaccines that use an adenovirus vector—seems pretty clear.
While so far the J&J vaccine has comprised only 5 percent of the total vaccinations given in the US, those numbers are going up. These clots are so strange that more may have gone unnoticed, or more may be yet to come—which means that epidemiologists might not know the true number of people with the problem (the numerator, as it were) or the true number of people who’ve received the J&J vaccine in the past couple of weeks (the denominator). And these kinds of clots—generally without the low platelet count—are already a rare but known complication of Covid-19, too, so even getting a background rate isn’t easy.
With just six events to work from, no one can tell if the fact that all of the people affected were women under age 50 is meaningful or not. Maybe it’s just coincidence, statistical noise. Or maybe young women are more vulnerable. If that’s true, their risk isn’t one in a million—because they were a smaller subgroup of vaccinated people overall, it’s orders of magnitude greater. Or maybe there’s some other risk factor, yet unidentified.
Now, maybe that risk is still worth it compared to getting Covid-19. That’s what European regulators concluded about the risks and benefits of the AstraZeneca vaccine, at least for certain groups of people. “I think the uniqueness of the constellation of symptoms and the fact that it has preferentially appeared in a group who is at lower risk of severe disease, that is driving some of the considerations,” says Natalie Dean, an biostatistician at the University of Florida. “It all comes back to a risk-benefit calculation, and these occur at the subpopulation level, not just at the whole population level.”
So why didn’t those regulators have their epidemiologists do that math in the background, quietly, rather than race to this national pause? The real question that the FDA and its advisers will have to answer is the same as for any medical intervention: How do the risks stack up next to the benefits? In the case of the J&J vaccine, the benefits are clear but the risks aren’t—at least, not entirely. And the risks and benefits are different for people in different age groups, in places with different levels of Covid-19 prevalence. Earlier this month, researchers at the Winton Centre for Risk and Evidence Communication tried to run these numbers for the AstraZeneca vaccine. For young people with low risk of exposure to the virus, the vaccine might’ve resulted in 1.1 blood clots per 100,000 people, roughly, and prevented just 0.8 Covid-related emergency room visits. But in people 60 to 69 years old with high risk, the vaccine could’ve been behind just 0.2 clots per 100,000 and prevented nearly 128 emergency room admissions. Seems like a good deal.
So much so, in fact, that some commentators have insisted that the FDA’s cautiousness borders on cowardice. (Officials say the rush was so they could start collecting better data, and to make sure people got appropriate treatment. The usual treatment for blood clots, a drug called heparin, can actually make this condition worse. “I wish we had more time to get everyone prepared and that this could go even more smoothly. As we learned about the issue with appropriate treatment, it was clear to us that we needed to alert the public,” said Anne Schuchat, principal deputy director of the CDC, at the Tuesday briefing. “The decision was based on the events that might occur between when we made that realization and when we got the word out.”)
For people who’ve faced similar risk-benefit calculations with medical interventions, that wasn’t good enough. On social media and in private chats, women noted that blood clots can be a side effect of hormonal birth control use. (A recent metaanalysis found that the pill can increase that risk, but different pill formulations have different effects, and age and other factors also play a role. That said, clots aren’t the only side effect of hormonal contraceptives, and the others can be onerous and chronic.)
The blood clots that oral contraceptives can cause are deep vein thrombosis, often in the legs—physiologically distinct from those associated with adenovirus-vector Covid vaccines. And, technically, there are more options for birth control than there are for dealing with Covid-19, though both have complicated risk-benefit matrixes with a lot of personal choice involved (and the consequences of both fall harder on women than men). But the pill certainly has fewer unknowns. “Hardly any condition has been studied as thoroughly as deep vein thrombosis and contraceptive steroid use. We’ve been at it a long time, while this is new with Covid and this vaccine, and there’s not much information,” says Philip Darney, director emeritus of the Bixby Center for Global Reproductive Health at UC San Francisco.
Part of the reason these risk-benefit calculations don’t match up is that Covid vaccines are unusual. In a way, more of the benefit of vaccination goes to others than to the person getting vaccinated—a public health, population-scale benefit that may outweigh an individual one. If it’s true that young women are most at risk of clotting from the J&J Covid vaccine, they’re also a group at relatively low risk from Covid-19 itself. That makes it especially hard to compare that risk to other risks that everyone, or subpopulations of everyone, might encounter every day.
All of which puts the FDA in a bind. Regulators could outright revoke the Johnson & Johnson emergency use authorization—very unlikely. They can say they’ve evaluated the risk, and it’s so small as to be far outweighed by the benefits of mass vaccination—full speed ahead. Or they can try the tricky messaging of saying some groups can get the J&J shot and others can’t, which risks alienating people who might get it and painting the vaccine designated in part for poor people as somehow less safe. These needles are all but unthreadable; it’s hard to walk back an “abundance of caution.”
Some proof: In the 1995 “pill scare,” similar concerns about birth control pills and blood clots led to hesitancy and unplanned pregnancies. “There are studies showing that the headlines, particularly in Europe, frightened women into stopping the use of their contraception, which led to unintended pregnancies and abortions,” Darney says. Eventually, contraceptive researchers improved the product, with lower hormone levels and a better sense of who was at greater risk for blood clots.
Even today, vaccination faces similar hesitancy. There’s the anti-vax sentiments common in white evangelical (and white wealthy) populations, which the J&J pause might well exacerbate out of sheer confirmation bias. More complex, though, is the distrust among the Black community after centuries of lack of access to health care and outright unethical treatment. “The communication around J&J was kind of, I don’t want to say tone deaf, but you have to understand, when you say the J&J vaccine is excellent for people who are disabled, homeless, mentally ill, addicted—they went down a list,” says Stephen B. Thomas, director of the Maryland Center for Health Equity at the University of Maryland-College Park and an expert in public health communication in the Black community. “The way they described it, my Black folks are saying, ‘Oh, that’s the one you’re going to send here, huh?’”
Thomas works via barber shops and beauty parlors with Black clienteles—a process he describes as iterative, getting information to people via town halls and bringing experts to those shops to overcome reasonable skepticism of institutional health care. “They recently, in the state of Maryland, started providing vaccine to primary care practices. That’s a great thing,” Thomas says. “But what vaccine do you think they gave the primary care practices? J&J. Because it’s simple, one and done. And they’ve already started giving the shots.”
These were the kinds of issues that came up in an emergency meeting on Wednesday of the FDA’s Advisory Committee on Immunization Practices, the group set up to figure out how best to deliver vaccines. After hours of presentations, ACIP members seemed to be leaning toward extending the pause on J&J indefinitely as they gathered the data they’d need to try to figure out the safety issues. But some representatives of other health care organizations who were also at the meeting warned against that path. “The extension of the pause will invariably result in the fact that the most vulnerable individuals in the United States, who were prime candidates of the J&J vaccine, will remain vulnerable,” said Nirav Shah, director of Maine’s Center for Disease Control and Prevention. “The most at risk will remain at risk.”
Grace Lee, an infectious disease physician at Stanford Children’s Health and an ACIP member, acknowledged the equity concerns Shah and others brought up. “It’s possible we may not have any more information, in which case I still think we’re going to have to make a decision or a recommendation,” Lee said. “My hope is that in the next week we can capture that in a more robust way.” The ACIP members ended the meeting without making a recommendation. They’ll reconvene in a week, maybe two, after gathering more data. No one knows what that data will say or how the pause will affect the momentum of the global vaccination effort. Vaccines in motion tend to remain in motion; the question is whether vaccines at rest will also tend to remain at rest.